Researchers at the University of Florida (UF) Health have identified a small molecule, Bac429, derived from gut bacteria, that demonstrated the ability to enhance the effectiveness of immune checkpoint inhibitors (ICIs) in mouse models of lung cancer. This discovery, published in Cell Reports Medicine, suggests a potential new combination therapy to improve patient response rates to immunotherapy, which are currently limited for many cancer types.
Immunotherapy Challenges in Cancer Treatment
Immune checkpoint inhibitors are a standard treatment option for various cancers, including non-small cell lung cancer. However, approximately 20% of patients respond to ICIs, while 80% do not. Some patients may also experience adverse effects without therapeutic benefit. This has prompted research into biological factors, such as the gut microbiome, that may influence immune responses to treatment outcomes.
Discovery and Identification of Bac429
The research originated from Christian Jobin's lab at UF, which investigates the relationship between gut microbiota and health. In 2018, initial funding from the Florida Academic Cancer Center Alliance and a collaboration with Moffitt Cancer Center provided access to human patient fecal samples from an immunotherapy clinical trial. Transplanting fecal samples from human immunotherapy responders into non-responsive mice resulted in improved treatment response in the mice, indicating a role for the gut microbiota in immunotherapy outcomes.
Following this observation, UF researchers developed a multistep pipeline to identify specific microbiota-derived molecules. This process involved purifying bacterial molecules, assessing their immune-stimulating capabilities, and isolating compounds with therapeutic potential. Through this methodology, a compound named Bac429 was isolated from gut microbes after screening over 180 bacterial strains.
Preclinical Findings in Lung Cancer Models
In preclinical studies using mouse models of lung cancer that were resistant to immunotherapy, Bac429 was administered alongside ICIs. The combination therapy resulted in a substantial inhibition of tumor growth, showing a 50% reduction compared to immunotherapy administered alone. Researchers hypothesize that Bac429 may promote antitumor immune responses by enhancing immune cell activation within the tumor microenvironment, potentially converting 'cold' (non-responsive) cancers into 'hot' (immunologically active) ones.
Rachel Newsome, Ph.D., a postdoctoral associate and the study's first author, noted that this small molecule could potentially increase patient responsiveness.
Future Development and Potential Applications
Researchers are currently developing drug derivatives of Bac429 and investigating its exact mechanism of action, with a hypothesis that the molecule interacts with immune cells in the gut, which then migrate to tumor sites. While the initial study focused on lung cancer, due to its high mortality rates and low response to ICIs, researchers suggest Bac429 could potentially be effective for other cancer types.
Bac429 is being considered for integration into existing treatment protocols, potentially administered prior to or concurrently with ICIs. The aim is to enhance immune responses without adding invasive procedures or significant toxicity.
UF is pursuing patent applications related to this work. Newsome and Jobin have also co-founded Bebi Therapeutics Inc., a biotech company formed from the university.
Broader Implications
The development of new microbiome-based drugs like Bac429 could influence the role of healthcare professionals, including pharmacists. Pharmacists may become instrumental in the implementation of new combination therapies, requiring an understanding of their mechanisms, potential drug-drug interactions, and the ability to explain combination therapy rationales to patients.
Funding and Publication
This research was published in Cell Reports Medicine on December 19. Funding sources included Gatorade royalties, the National Cancer Institute, the UF Health Cancer Institute, the UF College of Medicine, and the Florida Academic Cancer Center Alliance.